Multiple sclerosis (MS) is a neurological disease of major economic and social importance in which a viral etiology is still strongly suspected. Because of the historical importance of experimental animal models to understanding human diseases, investigation of multiple sclerosis models can be expected to lead to a clearer insight into the pathogenesis of this disease. Of the few available experimental animal models of virus-induced demyelination, Theiler's murine encephalomyelitis virus (TMEV) infection in mice is possibly the most relevant to MS. The prospect is that continued studies of this model will lead to innovative approaches which may ultimately link a specific virus(es) with MS and possibly provide approaches for the treatment of the disease. It is clear that a multidisciplinary approach is needed to answer relevant questions about the molecular pathogenesis of TMEV-induced demyelinating disease. Project 1 involves continuing studies of T cell immunity in the TMEV model. Using in vivo-derived polyclonal T cell populations and in vitro-propagated T cell clones and hybrids, effector phenotype, epitope specificity, T cell receptor usage, and immunopathologic potential of TMEV- specific peripheral and CNS-infiltrating CD4+ T cells subsets (i.e., Th1 and Th2 cells) and their soluble lymphokine products will be assessed in both susceptible and resistant mouse strains. In addition, the effects of specific (tolerance) and nonspecific (monoclonal antibody depletion) immunoregulation on the course of demyelination will be studied. Project 5 will further investigate the immunogenetic control of TMEV-induced demyelinating disease by continued identification and analysis of MHC and non-MHC genes associated with susceptibility and examine the role of active suppression in genetically resistant animals. Project 7 will continue experiments on introducing point mutations into TMEV surface residues to test whether amino acids in the putative viral receptor attachment site (pit) are involved in binding to the cellular receptor.